Cannabidivarin is anticonvulsant in mouse and rat.

Reading School of Pharmacy, University of Reading, Whiteknights, Reading, UK. a.j.hill@reading.ac.uk

Abstract

BACKGROUND AND PURPOSE:

Phytocannabinoids in Cannabis sativa have diverse pharmacological targets extending beyond cannabinoid receptors and several exert notable anticonvulsant effects. For the first time, we investigated the anticonvulsant profile of the phytocannabinoid cannabidivarin (CBDV) in vitro and in in vivo seizure models.

EXPERIMENTAL APPROACH:

The effect of CBDV (1-100 μM) on epileptiform local field potentials (LFPs) induced in rat hippocampal brain slices by 4-aminopyridine (4-AP) application or Mg(2+) -free conditions was assessed by in vitro multi-electrode array recordings. Additionally, the anticonvulsant profile of CBDV (50-200 mg·kg(-1) ) in vivo was investigated in four rodent seizure models: maximal electroshock (mES) and audiogenic seizures in mice, and pentylenetetrazole (PTZ) and pilocarpine-induced seizures in rats. The effects of CBDV in combination with commonly used antiepileptic drugs on rat seizures were investigated. Finally, the motor side effect profile of CBDV was investigated using static beam and grip strength assays.

CONCLUSIONS AND IMPLICATIONS:

These results indicate that CBDV is an effective anticonvulsant in a broad range of seizure models. Also it did not significantly affect normal motor function and, therefore, merits further investigation as a novel anti-epileptic in chronic epilepsy models.

LINKED ARTICLES:

This article is part of a themed section on Cannabinoids. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.167.issue-8.

Effects of CBDV on mES and audiogenic seizures in mice. (A) The effect of CBDV on the percentage of animals that exhibited tonic hindlimb extension in response to mES. (B–D) The effect of CBDV (50–200 mg·kg−1) on the percentage of animals that displayed tonic convulsions (B), remained seizure-free (C) or suffered mortality (D) as a result of audiogenic seizure induction. n = 10 in all cases, ***P ≤ 0.001.

Effects of CBDV on PTZ- and pilocarpine-induced seizures in rats. (A–D) The effect of CBDV on PTZ-induced seizures: seizure severity (A), mortality (B), the proportion of animals remaining seizure-free (C) and the onset latency (D). (E–H) The effect of CBDV on pilocarpine-induced convulsions: severity (E), mortality (F), the percentage of animals remaining seizure-free (G) and the onset latency (H). In (D and H), onset latency is presented as mean ± SEM In (A and E), median severity is represented by a thick horizontal line, the 25th and the 75th percentiles by the box and maxima and minima are represented by ‘whiskers’. n = 15 in all cases. *P ≤ 0.05, **P ≤ 0.01 and ***P ≤ 0.001.

Effects of co-administration of CBDV and AEDs on PTZ-induced seizures in rats. The effects of CBDV co-administration with VPA (A–D) or ESM (E–I) on PTZ-induced seizures: severity (A and E), mortality (B and F), the incidence of tonic–clonic seizures (C and G), onset latency (D and H) and (for CBDV + ESM only) the percentage of animals that remained seizure-free. In (D and H), onset latency is presented as mean ± SEM. In (A and E), median severity is represented by a thick horizontal line, the 25th and 75th percentiles by the box and maxima and minima are represented by ‘whiskers’. Significance of CBDV treatment is given in text. n = 15 in all cases. *P ≤ 0.05, **P ≤ 0.01 and ***P ≤ 0.001 for AED effects.

Effects of co-administration of CBDV and AEDs on pilocarpine-induced convulsions in rats. The effects of CBDV co-administration with VPA (A–D) or phenobarbital (E–I) on pilocarpine-induced convulsions: severity (A and E), mortality (B and F), the incidence of tonic–clonic convulsions (C and G), onset latency (D and H) and (for CBDV + phenobarbital only) the percentage of animals that remained seizure-free. In (D and H), onset latency is presented as mean ± SEM In (A and E), median severity is represented by a thick horizontal line, the 25th and 75th percentiles by the box and maxima and minima are represented by ‘whiskers’. Significance of CBDV treatment is given in text. n = 15 in all cases. *P ≤ 0.05, **P ≤ 0.01 and ***P ≤ 0.001 for AED effects.